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Mol Cell Biol, July 1998, p. 4131-4140, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Tyrosine 1101 of Tie2 Is the Major Site of Association of p85 and Is Required for Activation of Phosphatidylinositol 3-Kinase and Akt

Christopher D. Kontos,1 Thomas P. Stauffer,2 Wen-Pin Yang,3 John D. York,4 Liwen Huang,1 dagger Michael A. Blanar,3 Tobias Meyer,2 4 and Kevin G. Peters1 4 *

Departments of Medicine,1 Cell Biology,2 and Pharmacology and Cancer Biology,4 Duke University Medical Center, Durham, North Carolina 27710, and Department of Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 085433

Received 4 December 1997/Returned for modification 28 January 1998/Accepted 28 April 1998

Tie2 is an endothelium-specific receptor tyrosine kinase that is required for both normal embryonic vascular development and tumor angiogenesis and is thought to play a role in vascular maintenance. However, the signaling pathways responsible for the function of Tie2 remain unknown. In this report, we demonstrate that the p85 subunit of phosphatidylinositol 3-kinase (PI3-kinase) associates with Tie2 and that this association confers functional lipid kinase activity. Mutation of tyrosine 1101 of Tie2 abrogated p85 association both in vitro and in vivo in yeast. Tie2 was found to activate PI3-kinase in vivo as demonstrated by direct measurement of increases in cellular phosphatidylinositol 3-phosphate and phosphatidylinositol 3,4-bisphosphate, by plasma membrane translocation of a green fluorescent protein-Akt pleckstrin homology domain fusion protein, and by downstream activation of the Akt kinase. Activation of PI3-kinase was abrogated in these assays by mutation of Y1101 to phenylalanine, consistent with a requirement for this residue for p85 association with Tie2. These results suggest that activation of PI3-kinase and Akt may in part account for Tie2's role in both embryonic vascular development and pathologic angiogenesis, and they are consistent with a role for Tie2 in endothelial cell survival.

* Corresponding author. Mailing address: Box 3623, Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-2119. Fax: (919) 684-8591. E-mail: kgp{at}hodgkin.mc.duke.edu.

dagger Present address: Myriad Genetics, Inc., Salt Lake City, UT 84105.

Mol Cell Biol, July 1998, p. 4131-4140, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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